This invention relates to pyrrolopyrimidines, pharmaceutical compositions containing them, and their use in the treatment of stress-related and other diseases. The compounds have corticotropin-releasing factor (CRF) antagonist activity.
CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245 referring to peptides and pyrazolinones, respectively. The importance of CRF antagonists is set out in the literature, e.g. as discussed in U.S. Pat. No. 5,063,245, which is incorporated herein by reference. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), also incorporated herein by reference. Based on the research described in these two and other references, CRF antagonists are considered effective in the treatment of a wide range of diseases including stress-related illnesses, such as stress-induced depression, anxiety, and headache; irritable bowel syndrome; inflammatory diseases; immune suppression; human immunodeficiency virus (HIV) infections; Alzheimer""s disease; gastrointestinal diseases; anorexia nervosa; hemorrhagic stress; drug and alcohol withdrawal symptoms; drug addiction, and fertility problems.
The present invention relates to a compound of the formula 
and the acid addition salts thereof, wherein
B is XA wherein X is (CH2)n in which n is 0, 1 or 2, NH, O, S, or N(C1-C4 alkyl);
A is NR1R2, CR1R2R11, or C(xe2x95x90CR2R12)R1;
R1 is hydrogen, or mono or divalent C1-C6 aliphatic hydrocarbon which may be substituted by one or two substituents R7 independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, C1-C8 alkoxy, Oxe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94C(xe2x95x90O)xe2x80x94NH(C1-C4 alkyl), Oxe2x80x94C(xe2x95x90O)xe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), amino, NH(C1-C4 alkyl), N(C1-C2 alkyl)(C1-C4 alkyl), S(C1-C6 alkyl), N(C1-C4 alkyl)(C1-C4 alkyl), NH(C1-C4 alkyl), COOH, O(C1-C4 alkyl), NH(C1-C4 alkyl), N(C1-C4 alkyl)(C1-C2 alkyl), SH, CN, NO2, SO(C1-C4 alkyl), SO2(C1-C4 alkyl SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)(C1-C2 alkyl), and said mono or divalent C1-C6 aliphatic hydrocarbon may contain one or two double or triple bonds;
R2 is monovalent C1-C12 aliphatic hydrocarbon, aryl or (divalent C1-C10 aliphatic hydrocarbon)aryl wherein said aryl is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or (C1-C6 alkylene) cycloalkyl, wherein one or two methylene groups of said cycloalkyl may be independently replaced by one or two O, S or Nxe2x80x94Z radicals wherein Z is hydrogen, C1-C4 alkyl, benzyl or C1-C4 alkanoyl, wherein R2 may be substituted independently by from one to three of chloro, fluoro, or C1-C4 alkyl, or one of hydroxy, bromo, iodo, C1-C6 alkoxy, Oxe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94Cxe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), S(C1-C6 alkyl), NH2, NH(C1-C2 alkyl), N(C1-C2 alkyl) (C1-C4 alkyl), N(C1-C4 alkyl)xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl), NHC(xe2x95x90O)(C1-C4 alkyl), COOH, C(xe2x95x90O)xe2x80x94O(C1-C4 alkyl), C(xe2x95x90O)NH(C1-C4 alkyl), C(xe2x95x90O)N(C1-C4 alkyl)(C1-C2 alkyl), SH, CN, NO2, SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)(C1-C2 alkyl), and wherein said monovalent C1-C12 aliphatic hydrocarbon or said divalent C1-C10 aliphatic hydrocarbon may contain one to three double or triple bonds; or
when A is NR1R2 or CR1R2R11, the R1 and R2 may be taken together with the atom to which they are attached to form a saturated 4- to 8-membered ring optionally containing one or two double bonds or one or two O, S or Nxe2x80x94Z radicals wherein Z is hydrogen, C1-C4 alkyl, or C1-C4 alkanoyl;
R3 is hydrogen, monovalent C1-C6 aliphatic hydrocarbon, fluoro, chloro, bromo, iodo, hydroxy, amino, O(monovalent C1-C6 aliphatic hydrocarbon), NH(monovalent C1-C4 aliphatic hydrocarbon), N(monovalent C1-C4 aliphatic hydrocarbon)(C1-C2 alkyl), SH, S(monovalent C1-C4 aliphatic hydrocarbon), SO(monovalent C1-C4 aliphatic hydrocarbon), or SO2(monovalent C1-C4 aliphatic hydrocarbon), wherein said monovalent C1-C4 aliphatic hydrocarbon and said monovalent C1-C6 aliphatic hydrocarbon may contain one or two double or triple bonds and may be substituted by one to three substituents R8 independently selected from the group consisting of hydroxy, amino, C1-C3 alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NHC(xe2x95x90O)CH3, fluoro, chloro and C1-C3 alkylthio;
R4 and R6 are each independently hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, C1-C6 alkoxy, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C2 alkyl), SOn(C1-C6 alkyl) wherein n is 0, 1 or 2, cyano, hydroxy, carboxy, or amido, wherein said C1-C6 alkyls may be substituted by one to three of hydroxy, amino, carboxy, amido, NHC(xe2x95x90O)(C1-C4 alkyl), NH(C1-C4 alkyl), N(C1-C4 alkyl)(C1-C2 alkyl), C(xe2x95x90O)O(C1-C4 alkyl), C1-C3 alkoxy, C1-C3 alkylthio, fluoro, bromo, chloro, iodo, cyano or nitro;
R5 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, piperidinyl, piperazinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl, optionally containing one to three O, S or Nxe2x80x94Z radicals wherein Z is hydrogen, C1-C4 alkyl, C1-C4 alkanoyl, phenyl or phenylmethyl, wherein each one of the above groups may be substituted independently by from one to four of fluoro, chloro, monovalent C1-C6 aliphatic hydrocarbon, C1-C6 alkoxy or trifluoromethyl, or one of bromo, iodo, cyano, nitro, amino, NH(monovalent C1-C4 aliphatic hydrocarbon), N(monovalent C1-C4 aliphatic hydrocarbon)(C1-C2 alkyl), COO(monovalent C1-C4 aliphatic hydrocarbon), CO(monovalent C1-C4 aliphatic hydrocarbon), SO2NH(monovalent C1-C4 aliphatic hydrocarbon), SO2N(monovalent C1-C4 aliphatic hydrocarbon)(C1-C2 alkyl), SO2NH2, NHSO2(monovalent C1-C4 aliphatic hydrocarbon), S(monovalent C1-C6 aliphatic hydrocarbon), SO2(monovalent C1-C6 aliphatic hydrocarbon), wherein said monovalent C1-C4 aliphatic hydrocarbon and said monovalent C1-C6 aliphatic hydrocarbon may be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl;
R11 is hydrogen, hydroxy, fluoro, chloro, COO(C1-C2 alkyl), cyano, or CO(C1-C2 alkyl); and
R12 is hydrogen or monovalent C1-C4 aliphatic hydrocarbon; with the proviso that (1) when R5 is pbromophenyl, and at least two of R3, R4 and R6 are methyl, then B is not ethyl, ethoxy, S-ethyl, methylamino, dimethylamino, or hydroxyethylamino; and (2) when R5 is unsubstituted phenyl or unsubstitued cycloalkyl, then at least one of R3 and R4 is methyl, and B is not benzylamino, furfuryl (furanylmethyl)amino, or anilino (phenylamino).
Preferred compounds of the formula I of the invention are those wherein R1 is monovalent C1-C6 aliphatic hydrocarbon, which may be substituted by one or two of substituents R7 independently selected from the group consisting of hydroxy, fluoro, chloro, C1-C2 alkoxy, and OCxe2x80x94Oxe2x80x94(C1-C2 alkyl); those wherein R2 is monovalent C2-C6 aliphatic hydrocarbon or ethylenephenyl; those wherein R3 is hydrogen, methyl, ethyl, fluoro, chloro or methoxy; those wherein R4 and R6 are independently hydrogen, methyl, or ethyl; and those wherein R5 is phenyl substituted by two or three substituents, specifically 2,4,6-trichlorophenyl, 2,6-dichloro-4-trifluoromethyl, 2,4,6-trimethylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-methyl-4-iodophenyl, or 3,5-ditrifluoromethylphenyl.
Specific preferred compounds include:
n-butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
di-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
ethyl-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
diethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
n-butyl-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
2-(N-n-butyl-N-[2,5-dimethyl-7-(2,4,6-trimethyl phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-ethanol;
4-(1-ethyl-propyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;
n-butyl-ethyl-[2,5-dimethyl-7-(2,4-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine; and
2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl-4-yl-(1-ethyl-propyl)amine.
The invention also relates to a pharmaceutical composition for the treatment of illnesses induced or facilitated by corticotropin releasing factor which comprises a compound of the formula I as defined above in an amount effective in the treatment of said illnesses, and a pharmaceutically acceptable carrier, and a pharmaceutical composition for the treatment of inflammatory disorders, stress and anxiety related disorders including stress-induced depression and headache, irritable bowel syndrome, immune suppression, human immunedeficiency virus (HIV) infections, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems, which comprises a compound of the formula I as defined above in an amount effective in the treatment of said disorders, and a pharmaceutically acceptable carrier. Preferred compositions of the invention are those containing preferred compounds of formula I as described above.
The invention further relates to a method for the treatment of illnesses induced or facilitated by corticotropin releasing factor by administering to a subject in need of such treatment a compound of formula I as defined above in an amount effective in such treatment, and a method for the treatment of stress and anxiety related disorders including stress-induced depression and headache, irritable syndrome, inflammatory disorders, immune suppression, human immunedeficiency virus (HIV) infections, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems, particularly depression, by administering to a subject in need of such treatment a compound of formula I as defined above in an amount effective in such treatment. Preferred methods of the invention are those administering a preferred compound of the formula I as described above.
The invention also relates to an intermediate compound of the formula 
wherein
D is hydroxy or chloro,
R4 and R6 are each independently hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, C1-C6 alkoxy, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C2 alkyl), SOn(C1-C6 alkyl), wherein n is 0, 1 or 2, cyano, hydroxy, carboxy, or amido, wherein said C1-C6 alkyls may be substituted by one to three of hydroxy, amino, carboxy, amido, NHC(xe2x95x90O)(C1-C4 alkyl), NH(C1-C4 alkyl), N(C1-C4 alkyl)(C1-C2 alkyl), C(xe2x95x90O)O(C1-C4 alkyl), C1-C3 alkoxy, C1-C3 alkylthio, fluoro, bromo, chloro, iodo, cyano or nitro;
R5 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, piperdinyl, piperazinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl, optionally containing one to three of O, S or Nxe2x80x94Z wherein Z is hydrogen, C1-C4 alkyl, C1-C4 alkanoyl, phenyl or phenylmethyl, wherein each of the above groups may be substituted independently by from one to four of fluoro, chloro, C1-C6 alkyl, C1-C6 alkoxy or trifluoromethyl, or one of bromo, iodo, cyano, nitro, amino, NH(C1-C4 alkyl), N(C1-C4)(C1-C2 alkyl), COO(C1-C4 alkyl), CO(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)(C1-C2 alkyl), SO2NH2, NHSO2(C1-C4), S(C1-C6 alkyl), SO2(C1-C6 alkyl), wherein said C1-C4 alkyl and C1-C6 alkyl may be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl; with the proviso that R5 is not unsubstituted phenyl; and
R9 is hydrogen, C1-C6 alkyl or chloro, and a compound of the formula 
wherein
Y is CR1R2R11, CH2A or (CH2)2A;
A is NR1R2, CR1R2R11 or C(xe2x95x90CR2R12)R1;
R1 is hydrogen, or monovalent C1-C6 aliphatic hydrocarbon which may be substituted by one or two substituents R7 independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, C1-C8 alkoxy, Oxe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94C(xe2x95x90O)NH(C1-C4 alkyl), Oxe2x80x94C(xe2x95x90O)xe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), amino, NH(C1-C4 alkyl), N(C1-C2 alkyl)(C1-C4 alkyl), S(C1-C6 alkyl), N(C1-C4alkyl)C(xe2x95x90O)(C1-C4 alkyl), NHC(xe2x95x90O)(C1-C4 alkyl), COOH, C(xe2x95x90O)O(C1-C4 alkyl), C(xe2x95x90O)NH(C1-C4 alkyl), C(xe2x95x90O)N(C1-C4 alkyl)(C1-C2 alkyl), SH, CN, NO2, SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)(C1-C2 alkyl), and said monovalen C1-C6 aliphatic hydrocarbon may contain one or two double or triple bonds;
R2 is monovalent C1-C12 aliphatic hydrocarbon, aryl or (divalent C1-C10 aliphatic hydrocarbon)aryl wherein said aryl is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, oxazolyl, or benzoxazolyl; 3- to 8-membered cycloalkyl or (C1-C6 alkylene) cycloalkyl, wherein said cycloalkyl may contain one or two of O, S or Nxe2x80x94Z wherein Z is hydrogen, C1-C4 alkyl, benzyl or C1-C4 alkanoyl, wherein R2 may be substituted independently by from one to three of chloro, fluoro, or C1-C4 alkyl, or one of hydroxy, bromo, iodo, C1-C6 alkoxy, Oxe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94Cxe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), S(C1-C6 alkyl), NH2, NH(C1-C2 alkyl), N(C1-C2 alkyl) (C1-C4 alkyl), N(C1-C4)xe2x80x94C(xe2x95x90O)(C1-C4 alkyl), NHC(xe2x95x90O)(C1-C4), COOH, C(xe2x95x90O)O(C1-C4 alkyl), C(xe2x95x90O)NH(C1-C4 alkyl), C(xe2x95x90O)N(C1-C4 alkyl)(C1-C2 alkyl), SH, CN, NO2, SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)C1-C2 alkyl), and wherein said monovalent C1-C12 aliphatic hydrocarbon or said divalent C1-C10 aliphatic hydrocarbon may contain one to three double or triple bonds; or
when A is NR1R2 or CR1R2R11, then R1 and R2 taken together with the atom to which they are attached may form a saturated 4- to 8-membered optionally containing one or two double bonds or one or two of O, S or Nxe2x80x94Z wherein Z is hydrogen, C1-C4 alkyl, or C1-C4 alkanoyl;
R3 is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, hydroxy, amino, O(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C4 alkyl)(C1-C2 alkyl), SH, S(C1-C4 alkyl), SO(C1-C4 alkyl), or SO2(C1-C4 alkyl), wherein said C1-C4 alkyl and C1-C6 alkyl may contain from one or two double or triple bonds and may be substituted by from 1 to 3 substituents R8 independently selected from the group consisting of hydroxy, amino, C1-C3 alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NHC(xe2x95x90O)CH3, fluoro, chloro or C1-C3 alkylthio;
R4 and R6 are each independently hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, C1-C6 alkoxy, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C2 alkyl), SOn(C1-C6 alkyl), wherein n is 0, 1 or 2, cyano, hydroxy, carboxy, or amido, wherein said C1-C6 alkyls may be substituted by one to three of hydroxy, amino, carboxy, amido, NHC(xe2x95x90O)(C1-C4 alkyl), NH(C1-C4 alkyl), N(C1-C4 alkyl)(C1-C2 alkyl), C(xe2x95x90O)O(C1-C4 alkyl), C1-C3 alkoxy, C1-C3 alkylthio, fluoro, bromo, chloro, iodo, cyano or nitro;
R5 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, piperidinyl, piperazinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl, optionally containing one to three of O, S or Nxe2x80x94Z wherein Z is hydrogen, C1-C4 alkyl, C1-C4 alkanoyl, phenyl or phenylmethyl, wherein each one of the above groups may be substituted independently by from one to four of fluoro, chloro, C1-C6 alkyl, C1-C6 alkoxy or trifluoromethyl, or one of bromo, iodo, cyano, nitro, amino, NH(C1-C4 alkyl), N(C1-C4)(C1-C2 alkyl), COO(C1-C4 alkyl), CO(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)(C1-C2 alkyl), SO2NH2, NHSO2(C1-C4 alkyl), S(C1-C6 alkyl), SO2(C1-C6 alkyl), wherein said C1-C4 alkyl and C1-C6 alkyl may be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl; with the proviso that R5 is not unsubstituted phenyl;
R11 is hydrogen, hydroxy, fluoro, chloro, COO(C1-C2 alkyl), cyano, or CO(C1-C2 alkyl); and
R12 is hydrogen or C1-C4 alkyl.
Whenever reference is made herein to 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl containing one to three of O, S or Nxe2x80x94Z, it is understood that the oxygen and sulfur ring atoms are not adjacent to each other. The three membered cycloalkyl has just one O, S or Nxe2x80x94Z. An example of a six-membered cycloalkyl having O and N is morpholinyl.
Whenever R2 or R5 is a heterocyclic group, the attachment of the group is through a carbon atom.
The terms xe2x80x9cmonovalent aliphatic hydrocarbonxe2x80x9d and xe2x80x9cdivalent aliphatic hydrocarbonxe2x80x9d have been used herein, usually associated with an indication of the number of carbon atoms present, e.g., xe2x80x9cmonovalent C1-C12 aliphatic hydrocarbonxe2x80x9d. These terms have been used herein to define R1, R2, R3, and R5, where they have also been associated with an indication that they include, optionally, unsaturation as well as with an expression of what type and extent of unsaturation is contemplated, e.g., by such language as xe2x80x9cmay contain one or two double or triple bondsxe2x80x9d. The term xe2x80x9caliphatic hydrocarbonxe2x80x9d as thus used is intended to mean a straight or branched chain of carbon and hydrogen atoms that has a linear conformation rather than a cyclic or ring conformation, which is characteristic of aromatic hydrocarbons.
The aliphatic hydrocarbon chain may be saturated, i.e., it is an alkane, or it may be unsaturated, i.e., it is an alkene (double bond) or an alkyne (triple bond). It will be understood that where the aliphatic hydrocarbon is unsaturated by reason of the presence of one double or triple bond, that at least two carbon atoms are required to be present in the hydrocarbon chain; and that where two or more double and/or triple bonds are present, that at least three or more carbon atoms will be required in the hydrocarbon chain. The aliphatic hydrocarbon chain may also be monovalent or divalent. Where it is monovalent, it is a radical, e.g., where R2 is defined as xe2x80x9cmonovalent C1-C12 aliphatic hydrocarbonxe2x80x9d, the R2 substituent comprises an alkane-yl (alkyl), alkene-yl or alkyne-yl moiety directly attached to the nucleus of the compound of formula I by a single, covalent bond. Where the aliphatic hydrocarbon is divalent, it is a bridging element, e.g., where R2 is defined as xe2x80x9c(divalent C1-C10 aliphatic hydrocarbon)arylxe2x80x9d, the R2 substituent comprises an alkane-di-yl, alkene-di-yl or alkyne-di-yl moiety attached to said nucleus by a single, covalent bond, and at the same time attached to the xe2x80x9carylxe2x80x9d moiety by a single, covalent bond, whereby it forms a bridge between said aryl moiety and said nucleus.
Whenever reference is made herein to xe2x80x9camidoxe2x80x9d as a substituent moiety, e.g., in the definitions of substituents R4 and R6 to the nucleus of the compounds of formula I, it is understood that there is included within the meaning of that term as used herein a substituent moiety having one of the following formulas: xe2x80x94C(xe2x95x90O)NH2; xe2x80x94C(xe2x95x90O)NH(C1-C4 alkyl); or xe2x80x94C(xe2x95x90O)N(C1-C4 alkyl)(C1-C2 alkyl).
The compounds of formula I wherein B is NR1R2, NHA, N(C1-C4 alkyl)A, OA, SA, A is NR1R2, CR1R2R11 or C(xe2x95x90CR2R12)R1, and R3 is hydrogen, C1-C6 alkyl or chloro (hereafter R9) may be prepared by reaction of a compound of the formula 
wherein R4 and R5 are as defined above with reference to formula I, with an amine of the formula NHR1R2, NH2A, NH(C1-C4 alkyl)A, HOA or HSA wherein R1 and R2 are as defined with reference to formula I. The reaction is carried out in a solvent in the presence of a base at a temperature of between about 0xc2x0 to about 150xc2x0 C. Suitable solvents are organic solvents such as acetonitrile, dimethylsulfoxide, acetone, C2-C15 alkyl alcohol, tetrahydrofuran, chloroform, benzene, xylene or toluene, preferably acetontrile or dimethylsulfoxide.
When B is NHA, NR1R2 or N(C1-C4 alkyl)A, an excess of NH2A, NHR1R2 or NH(C1-C4 alkyl)A, respectively, is used. Other bases such as potassium carbonate or tri-(C1-C6)alkyl amine may be used. The reaction is carried out at a temperature of about 75xc2x0 to 150xc2x0 C. When the reaction is carried out in the presence of a base, such as sodium hydride or potassium C1-C4 alkoxide, a molar equivalent of the amine is used. When B is OA or SA, a base which is capable of deprotonation of HOA or HSA may be used, such as an alkali metal hydride such as sodium hydride, or an organometallic base such as sodium diisopropylamide, sodium bis(trimethylsily)amide, lithium diisopropylamide, lithium bis(trimethylsily)amide, sodium C1-C4 alkoxide or n-butylithium. The solvent used is dry tetrahydrofuran, dimethylsulfoxide or methylene chloride, and the reaction temperature is between about xe2x88x9278xc2x0 C. and the reflux temperature of the reaction mixture, preferably 0xc2x0 C. to 80xc2x0 C.
The compounds of formula I wherein B is NR1R2, NHA, N(C1-C4 alkyl)A, OA, SA and A is NR1R2, CR1R2R11 or C(xe2x95x90CR2R12)R1 and R3 is the groups other than R9 (hereafter R10) may be prepared by reacting a compound of the formula I wherein R3 is chloro with a nucleophile of the formula R10H with or without an organic or inorganic base. Suitable bases include sodium, sodium hydride, and alkali metal hydroxide such as potassium hydroxide, and weaker bases such as potassium carbonate or triethylamine. The latter are generally used when R10H is alkanol, C1-C6 alkanethiol, an amine, e.g. NH(C1-C6 alkyl), or tetrahydrobutyl ammonium fluoride. Suitable solvents are dimethylsulfoxide, acetonitrile, C1-C5 alkyl alcohol, tetrahydrofuran, benzene, toluene or methylene chloride.
The compounds of formula II as defined above may be prepared by reacting the corresponding 4-hydroxy compound of formula III (not shown) with an excess of phosphorus oxychloride or thionyl chloride at temperatures between about 60 to 140xc2x0 C., conveniently at the reflux temperature of the reaction mixture. When the reaction is carried out in a solvent, suitable solvents are halogenated alkanes, such as methylene chloride or chloroform. The reaction may be in the presence of a base such as N,N-diethylaniline, trimethylamine or potassium carbonate.
The compounds of formula III as defined above may be prepared by conventional methods as described in the prior art. Alternatively, the compounds of formula III wherein R9 is hydrogen may be prepared by reaction of a compound of the formula 
wherein R4, R5, and R6 are as defined with reference to formula I with formic acid at a temperature between about 60 to 140xc2x0 C., preferably at the reflux temperature of the reaction mixture.
The compounds of formula III wherein R9 is C1-C6 alkyl (hereafter R13) may be prepared by reacting a compound of formula IV with R13COOCOR13 in R13COOH wherein R13 is C1-C6 alkyl at a temperature between 25xc2x0 to 120xc2x0 C., preferably at the reflux temperature of the reaction mixture. The compounds of formula III wherein R9 is hydroxy may be prepared by reacting a compound of formula IV with chlorosulfonyl isocyanate in an appropriate solvent at temperature between xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably at xe2x88x9220xc2x0 C. to 60xc2x0 C., followed by acid hydrolysis. The appropriate solvents include methylene chloride, dimethyl formamide, tetrahydrofuran, and toluene, preferably dimethyl formamide or methylene chloride. The above formed compounds wherein R9 is hydrogen, C1-C6 alkyl or hydroxy may be heated in aqueous acid to give the compounds of formula III. The appropriate aqueous acids are 85% phosphoric acid, hydrochloric acid, sulfuric acid, or acetic acid, preferably 85% phosphoric acid. The reaction is generally carried out at about 25 to 150xc2x0 C., preferably 80 to 130xc2x0 C. Alternatively, the formed compounds may be heated with phosphorous pentoxide and N,N-dimethylcyclohexanamine at about 150 to 200xc2x0 C.
The compounds of formula IV may be prepared by conventional methods.
The compounds of formula I wherein B is CR1R2R11 or CH2A, (CH2)2A wherein A is as defined above with reference to formula I, and R3 is hydrogen, C1-C6 alkyl, or hydroxy (hereafter R14) may be prepared, as depicted in Scheme 1, by heating a compound of the formula VI, wherein R14 is hydrogen, C1-C6 alkyl, or amino and R1, R2, R11, R4, R9, and R6 are as defined above, with ammonium chloride and R14CONH2 at reflux temperatures.
The compounds of formula I wherein B is CR1R2R11 CH2A, or (CH2)2A wherein A is as defined above with reference to formula I and R3 is as defined above other than hydrogen, C1-C6 alkyl, or hydroxy, may be prepared by reacting the 2-chloro derivatives of formula I wherein R3 is chloro (formula I-B, not shown) with a nucleophile of formula R15H with or without an organic or inorganic base by the method described previously for the reaction with R10H, wherein R15 is R3 other than hydrogen, C1-C6 alkyl, hydroxy, and chloro. The compounds of formula I-B may be prepared by a method analogous to that for the conversion of compounds III to compounds II.
The compounds of formula VI may be prepared, as shown in Scheme I, starting from compounds of the formula V by methods analogous to those for the conversion of compounds IV to compounds III.
The compounds of formula V may be prepared by methods analogous to the conventional methods used for the preparation of compounds of formula IV by using YCOCH2CN instead of malonitrile, wherein Y is CR1R2R11, CH2A or (CH2)2A wherein A is as defined above with reference to formula I. 
The acid addition salts of the compounds of formula I are prepared in a conventional manner by treating a solution or suspension of the free base of formula I with one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration or crystallization techniques are employed in isolating the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toluenesulfonic, mandelic, di-p-toluoyl-L-tartaric and related acids.
The novel compound of the invention of formula I may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple, e.g. up to three, doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. The pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
For parenteral administration, solutions of the novel compound of formula I in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Additionally, it is possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes and ointments in accordance with standard pharmaceutical practice.
The effective dosage for the compound of formula I depends on the intended route of administration and other factors such as age and weight of the patient, as generally known to a physician. The dosage also depends on the illness to be treated. The daily dosage will generally range from about 0.1 to 50 mg/kg of the body weight of the patient to be treated. For treatment of inflammatory diseases about 0.1 to about 100 mg/kg will be needed, for Alzheimer""s disease, about 0.1 to about 50 mg/kg, as well as for gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, etc.
The methods for testing the compounds for formula I for their CRF antagonist activity are according to the procedures of Endocrinology, 116, 1653-1659 (1985) and Peptides, 10, 179-188 (1985) which determine the binding activity of a test compound to a CRF receptor. The binding activity for the compounds of formula I generally ranges from about 0.2 nanomolar to about 10 micromolar.